The controlled responsive delivery of IL-2/Fc enabled the safe administration of repeated doses of the stimulant cytokine with no overt toxicity and improved efficacy against melanoma metastases in a mice model.
Thus, CD122-biased IL-2 approaches constitute a novel class of immunotherapy for metastatic cancer that has the potential to complement and increase the efficacy of other antitumour strategies.
Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases.
Under the guidance of tumor-oriented chemokines, liposome-anchored Treg cells can be leveraged to migrate and infiltrate the acidic tumor microenvironment, where pH-sensitive liposomes release the loaded cargos [comprising interleukin-2, programmed cell death ligand 1 antibody (PD-L1), and imiquimod], provoke dramatic dendritic cell maturation, block the PD-1/PD-L1 immune-checkpoint, elevate the frequency of infiltrating CD8<sup>+</sup> effector T cells, and collectively contribute to potent inhibition of in situ and metastatic tumors.
PTX and IL-2 co-loaded TSNs exhibited significant inhibition on tumor growth and metastasis, and prolonged overall survival for tumor-bearing mice compared with the corresponding monotherapies.
The combination of <i>Cish</i> deficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis.
There were only three pairwise correlations between the produced cytokines that were specific to MAC with LN metastasis: IL-2 and IFN-γ, IL-6 and GM-CSF, and IL-8 and GM-CSF.
The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis.
Pre-treatment LDH values and site(s) of metastatic disease may be useful markers to select patients at greater likelihood of benefit to HD IL-2 therapy.
The IL-2 mutant shows a higher antimetastatic effect than does wtIL-2 in several transplantable tumor models: the experimental metastasis model of MB16F0 melanoma and the experimental and spontaneous metastasis models for the mouse pulmonary carcinoma 3LL-D1222.
Fractalkine (CX3CL1)- and interleukin-2-enriched neuroblastoma microenvironment induces eradication of metastases mediated by T cells and natural killer cells.
Production of cytokines such as IL-2 and IFN-gamma were significantly enhanced by the administration of Punarnavine compared to the untreated metastatic tumor-bearing control.
Finally, the 264scTCR/IL-2 fusion protein can be used to stain tumor cells and is capable of reducing lung metastases in an experimental model of metastasis.
Patients with lymphnode metastases and poorly differentiated tumours expressed IL-4 and IL-10 more frequently with concomitant suppression of IFN-gamma and IL-2 genes.
Therefore, up-regulation of TIMP-1 expression by IL-2 likely contributed to the additive effect of IL-2 and TIMP-1 in reducing metastatic disease in the animal model.
Serial sampling by fine-needle aspirates (FNAs) of identical metastases from patients affected with metastatic melanoma and undergoing IL-2-based vaccination allowed prospective measurement of IL-10, TGF-beta1, TGF-beta2 and IFN-gamma transcriptional levels assessed by quantitative real-time PCR.
In C57Bl/6 mice harboring lung metastases of melanoma, the administration of three sequential i.v. injections of 10(5) endothelial cells expressing a human interleukin 2 transgene abrogated the tumor metastases and prolonged survival of the animals.